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Activation of HIF-1alpha (hypoxia inducible factor-1a) prevents dry eye-induced acinar cell death in the lacrimal gland

 Y Seo  ;  Y W Ji  ;  S M Lee  ;  J Shim  ;  H Noh  ;  A Yeo  ;  C Park  ;  M S Park  ;  E J Chang  ;  H K Lee 
 CELL DEATH & DISEASE, Vol.5(6) : 1309, 2014 
Journal Title
Issue Date
Animals ; Autophagy* ; Cyclooxygenase 2/genetics ; Cyclooxygenase 2/metabolism ; Female ; Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis* ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Lacrimal Apparatus/metabolism* ; Lacrimal Apparatus/pathology ; Matrix Metalloproteinase 9/genetics ; Matrix Metalloproteinase 9/metabolism ; Mice ; Mice, Knockout ; Sjogren's Syndrome/genetics ; Sjogren's Syndrome/metabolism* ; Sjogren's Syndrome/pathology ; Sjogren's Syndrome/prevention & control
The pathogenesis of immune-mediated lacrimal gland (LG) dysfunction in Sjögren’s syndrome has been thoroughly studied. However, the majority of dry eye (DE) is not related to Sjögren type, and its pathophysiology remains unclear. The purpose of this study was to determine and investigate the protective mechanisms against DE stress in mice. DE induced prominent blood vessel loss without apoptosis or necrosis in the LG. Autophagic vacuoles, distressed mitochondria, and stressed endoplasmic reticulum were observed via electron microscopy. Immunoblotting confirmed the increase in autophagic markers. Glycolytic activities were enhanced with increasing levels of succinate and malate that, in turn, activated hypoxia-inducible factor (HIF)-1α. Interestingly, the areas of stable HIF-1α expression overlapped with COX-2 and MMP-9 upregulation in LGs of DE-induced mice. We generated HIF-1α conditional knockout (CKO) mice in which HIF-1α expression was lost in the LG. Surprisingly, normal LG polarities and morphologies were completely lost with DE induction, and tremendous acinar cell apoptosis was observed. Similar to Sjögren’s syndrome, CD3+ and CD11b+ cells infiltrated HIF-1α CKO LGs. Our results show that DE induced the expression of HIF-1α that activated autophagy signals to prevent further acinar cell damage and to maintain normal LG function.
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1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Noh, Hae Mi(노혜미)
Park, Min Soo(박민수) ORCID logo https://orcid.org/0000-0002-4395-9938
Yeo, Areum(여아름)
Lee, Hyung Keun(이형근) ORCID logo https://orcid.org/0000-0002-1123-2136
Ji, Yong Woo(지용우) ORCID logo https://orcid.org/0000-0002-7211-6278
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